Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma (original) (raw)

• Letter
• Published: 10 August 2015
• Jared P Steranka1,
• Alvin Makohon-Moore1,2,
• Allison Moyer1,
• Peilin Shen1,
• Reema Sharma1,
• Zachary A Kohutek3,
• Cheng Ran Huang4,
• Daniel Ahn1,
• Paolo Mita5,6,
• Martin S Taylor6,
• Norman J Barker1,
• Ralph H Hruban1,7,8,
• Christine A Iacobuzio-Donahue1,2,7,8,
• Jef D Boeke4,5,6,7,9 &
• …
• Kathleen H Burns1,4,6,7

Nature Medicine volume 21, pages 1060–1064 (2015)Cite this article

• 6623 Accesses
• 145 Citations
• 43 Altmetric
• Metrics details

Subjects

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed after the disease has metastasized; it is among the most lethal forms of cancer. We recently described aberrant expression of an open reading frame 1 protein, ORF1p, encoded by long interspersed element-1 (LINE-1; L1) retrotransposon, in PDAC1. To test whether LINE-1 expression leads to somatic insertions of this mobile DNA, we used a targeted method to sequence LINE-1 insertion sites in matched PDAC and normal samples. We found evidence of 465 somatic LINE-1 insertions in 20 PDAC genomes, which were absent from corresponding normal samples. In cases in which matched normal tissue, primary PDAC and metastatic disease sites were available, insertions were found in primary and metastatic tissues in differing proportions. Two adenocarcinomas secondarily involving the pancreas, but originating in the stomach and duodenum, acquired insertions with a similar discordance between primary and metastatic sites. Together, our findings show that LINE-1 contributes to the genetic evolution of PDAC and suggest that somatic insertions are acquired discontinuously in gastrointestinal neoplasms.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

• Purchase on SpringerLink
• Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

• Log in
• Learn about institutional subscriptions
• Read our FAQs
• Contact customer support

Similar content being viewed by others

References

1. Rodic´, N. et al. Long interspersed element-1 protein expression is a hallmark of many human cancers. Am. J. Pathol. 184, 1280–1286 (2014).
   Article Google Scholar
2. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
   Article CAS Google Scholar
3. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
   Article CAS Google Scholar
4. Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).
   Article CAS Google Scholar
5. Burns, K.H. & Boeke, J.D. Human transposon tectonics. Cell 149, 740–752 (2012).
   Article CAS Google Scholar
6. Beck, C.R., Garcia-Perez, J.L., Badge, R.M. & Moran, J.V. LINE-1 elements in structural variation and disease. Annu. Rev. Genomics Hum. Genet. 12, 187–215 (2011).
   Article CAS Google Scholar
7. Hancks, D.C. & Kazazian, H.H. Jr. Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 22, 191–203 (2012).
   Article CAS Google Scholar
8. Iskow, R.C. et al. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141, 1253–1261 (2010).
   Article CAS Google Scholar
9. Ewing, A.D. & Kazazian, H.H. Jr. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 20, 1262–1270 (2010).
   Article CAS Google Scholar
10. Murphy, K.M. et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 62, 3789–3793 (2002).
    CAS PubMed Google Scholar
11. Jones, S. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324, 217 (2009).
    Article CAS Google Scholar
12. Whitcomb, D.C. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat. Genet. 14, 141–145 (1996).
    Article CAS Google Scholar
13. Whelan, A.J., Bartsch, D. & Goodfellow, P.J. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N. Engl. J. Med. 333, 975–977 (1995).
    Article CAS Google Scholar
14. Ostertag, E.M. & Kazazian, H.H. Jr. Biology of mammalian L1 retrotransposons. Annu. Rev. Genet. 35, 501–538 (2001).
    Article CAS Google Scholar
15. Ostertag, E.M. & Kazazian, H.H. Jr. Twin priming: a proposed mechanism for the creation of inversions in L1 retrotransposition. Genome Res. 11, 2059–2065 (2001).
    Article CAS Google Scholar
16. Goodier, J.L., Ostertag, E.M. & Kazazian, H.H. Jr. Transduction of 3′-flanking sequences is common in L1 retrotransposition. Hum. Mol. Genet. 9, 653–657 (2000).
    Article CAS Google Scholar
17. Beck, C.R. et al. LINE-1 retrotransposition activity in human genomes. Cell 141, 1159–1170 (2010).
    Article CAS Google Scholar
18. Solyom, S. et al. Extensive somatic L1 retrotransposition in colorectal tumors. Genome Res. 22, 2328–2338 (2012).
    Article CAS Google Scholar
19. Shukla, R. et al. Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 153, 101–111 (2013).
    Article CAS Google Scholar
20. Lee, E. et al. Landscape of somatic retrotransposition in human cancers. Science 337, 967–971 (2012).
    Article CAS Google Scholar
21. Helman, E. et al. Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res. 24, 1053–1063 (2014).
    Article CAS Google Scholar
22. Tubio, J.M. et al. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345, 1251343 (2014).
    Article Google Scholar
23. Stephens, P.J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).
    Article CAS Google Scholar
24. Evrony, G.D. et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012).
    Article CAS Google Scholar
25. Huang, C.R. et al. Mobile interspersed repeats are major structural variants in the human genome. Cell 141, 1171–1182 (2010).
    Article CAS Google Scholar
26. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S.L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).
    Article Google Scholar
27. Ji, H. et al. An integrated software system for analyzing ChIP-chip and ChIP-seq data. Nat. Biotechnol. 26, 1293–1300 (2008).
    Article CAS Google Scholar
28. Amikura, K., Kobari, M. & Matsuno, S. The time of occurrence of liver metastasis in carcinoma of the pancreas. Pancreatol. 17, 139–146 (1995).
    CAS Google Scholar
29. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).
    Article CAS Google Scholar
30. Mootha, V.K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
    Article CAS Google Scholar

Download references

Acknowledgements

This work was started by funding from the Sol Goldman Pancreatic Cancer Research Center (K.H.B. and N.R.) and supported also by the Fred and Janet Sanfilippo Fund in the Department of Pathology at the Johns Hopkins University School of Medicine (N.R.); a Burroughs Wellcome Fund Career Award for Biomedical Scientists Program (K.H.B.); and US National Institutes of Health awards F31CA180682 (A.M.-M.), R01CA163705 (K.H.B.), R01GM103999 (K.H.B.), P50CA62924 (R.H.H. and C.A.I.-D.), R01CA179991 (C.A.I.-D.), as well as the National Institute of General Medical Sciences Center for Systems Biology of Retrotransposition P50GM107632 (K.H.B. and J.D.B.). Computational resources were provided through the National Science Foundation–funded MRI-R2 project #DBI-0959894. The authors would like to thank H. Kazazian, S. Solyom and A. Ewing for their helpful discussion. This work is dedicated to Dr. Frank Kretzer.

Author information

Authors and Affiliations

1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
   Nemanja Rodić, Jared P Steranka, Alvin Makohon-Moore, Allison Moyer, Peilin Shen, Reema Sharma, Daniel Ahn, Norman J Barker, Ralph H Hruban, Christine A Iacobuzio-Donahue & Kathleen H Burns
2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
   Alvin Makohon-Moore & Christine A Iacobuzio-Donahue
3. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
   Zachary A Kohutek
4. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
   Cheng Ran Huang, Jef D Boeke & Kathleen H Burns
5. Department of Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
   Paolo Mita & Jef D Boeke
6. High Throughput (HiT) Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
   Paolo Mita, Martin S Taylor, Jef D Boeke & Kathleen H Burns
7. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland, USA
   Ralph H Hruban, Christine A Iacobuzio-Donahue, Jef D Boeke & Kathleen H Burns
8. The Sol Goldman Center for Pancreatic Cancer Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
   Ralph H Hruban & Christine A Iacobuzio-Donahue
9. Institute for Systems Genetics, New York University Langone School of Medicine, New York, New York, USA
   Jef D Boeke

Authors

1. Nemanja Rodić
2. Jared P Steranka
3. Alvin Makohon-Moore
4. Allison Moyer
5. Peilin Shen
6. Reema Sharma
7. Zachary A Kohutek
8. Cheng Ran Huang
9. Daniel Ahn
10. Paolo Mita
11. Martin S Taylor
12. Norman J Barker
13. Ralph H Hruban
14. Christine A Iacobuzio-Donahue
15. Jef D Boeke
16. Kathleen H Burns

Contributions

N.R., R.H.H., C.A.I.-D., J.D.B. and K.H.B. conceived of the project; N.R., A.M.-M. and C.A.I.-D. obtained tissues and reviewed histology; J.P.S., A.M., P.S. and P.M. designed and performed molecular-biology assays; N.R., R.S., M.S.T. and N.J.B. performed and reviewed immunostains; Z.A.K., C.R.H. and D.A. designed and performed sequence analysis; N.R., J.P.S., J.D.B. and K.H.B. interpreted data; J.P.S. summarized data for the supplementary tables; N.R. and K.H.B. wrote the manuscript. All authors contributed edits and approved of the final manuscript.

Corresponding author

Correspondence toKathleen H Burns.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Rodić, N., Steranka, J., Makohon-Moore, A. et al. Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma.Nat Med 21, 1060–1064 (2015). https://doi.org/10.1038/nm.3919

Download citation

• Received: 16 January 2015
• Accepted: 12 July 2015
• Published: 10 August 2015
• Issue date: September 2015
• DOI: https://doi.org/10.1038/nm.3919

This article is cited by